There exists a selective vulnerability in the distribution of neuropathology in Alzheimer's disease (AD). We used this neuropathologic characteristic to stage the progression of beta- amyloid deposition within neuritic plaques, and its relationship to neuropeptide containing dystrophic neurites and neurofibrillary tangles (NFTs). Beta-amyloid appears in diffuse plaques prior to the development of dystrophic neurites and the deposition of haired helical filaments. The relationship between neuropathology and apoptosis (programmed cell death) was evaluated in the hippocampus of AD brains, revealing a strong correlation between presence of apoptotic nuclei and AD. However, direct evidence of apoptosis in NFTs was not observed. A more thorough evaluation of other brain regions will elucidate the role of apoptosis in AD. We have developed several approaches to elucidating the molecular basis of selective vulnerability in AD. Monoclonal antibodies were generated against the entorhinal cortex or basolateral amygdala using the SOFISTIC technique. These antibodies label specific subcellular compartments in apparently healthy neurons as well as neurofibrillary tangles. Another approach has been to probe the regional expression of homeobox genes as a means to understand the mechanism of regional differentiation in the cerebral cortex. Analysis of the relationship between oxidative metabolism and AD revealed a deficit the level of COX enzyme activity and MRNA expression in selectively vulnerable brain regions. Neuropathologic analysis of AD patients identified clinically with leukoencephalopathy did not support a direct vascular role in the etiology of the disease. Amyloid staining revealed severe cerebral amyloid angiopathy without involvement of white matter vessels. Thus, the increased amyloid burden in the cerebral vasculature does not appear to account for clinically observed leukoencephalopathy in AD patients.